TGF-a is expressed as a transmembrane protein, and cells can release soluble TGF-a into the medium as a result of the regulated proteolytic cleavage of the ectodomain. The laboratory has identified several transmembrane and cytoplasmic proteins that interact with TM TGF-a and obtained the full-length cDNAs. The hypothesis is that these associated proteins regulate intracellular transport, maturation, cell surface presentation and ectodomain cleavage of TM TGF-a. The application has four specific aims, each focusing on a defined protein that associates with TM TGF-a. Aim 1 will characterize the association of the tetraspan protein CD9. Aims 2 and 3 will focus on the biochemical and functional characterization of human homologs of Drosophila Rhomboid and Cornichon. Aim 4 focuses on the functional characterization of p59, a PDZ containing protein implicated in TM TGF-a transport through the Golgi